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Journal of Thrombosis and Haemostasis, 1: 171–177 Protective effects of vitamin C on endothelium damageand platelet activation during myocardial infarctionin patients with sustained generation ofcirculating microparticles O . M O R E L , Ãy L . J E S E L , à B . H U G E L , yz M - P D O U C H E T , à M . Z U P A N , à M . C H A U V I N , à J - M F R E Y S S I N E T yz andF . T O T I yz§ÃFe´de´ration de Cardiologie des Hoˆpitaux Universitaires de Strasbourg, France; yInstitut d’He´matologie et d’Immunologie, Universite´ Louis Pasteur,Strasbourg, France; zU. 143 INSERM, Le Kremlin-Biceˆtre; and §Faculte´ de Me´decine Paris-Sud, Le Kremlin-Biceˆtre, France thrombin generation [5]. Their procoagulant potential relies on Summary. During myocardial infarction (MI), high levels of phosphatidylserine (PhtdSer), an aminophospholipid translo- circulating procoagulant microparticles (MP) shed from endo- cated to the external membrane leaflet, and on the possible thelial cells and platelets diffuse prothrombotic and proinflam- presence of membrane tissue factor (TF), the major cellular matory potentials crucial for the coronary prognosis. In addition activator, expressed by smooth muscle cells, fibroblasts, mono- to conventional treatments, we evaluated whether vitamin C cytes and activated endothelial cells. High amounts of circulat- treatment could modify circulating levels of procoagulant MP.
ing procoagulant MP, shed mainly from platelets and Upon admission, 61 patients with MI were prospectively ran- endothelial cells, are detected during acute coronary syndrome domized for immediate additional vitamin C treatment. Circu- [6] and may influence the coronary prognosis [7].
lating MP were quantified by functional prothrombinase assay Oxidative stress may account for a significant proportion in before and after 5 days of vitamin C administration (1 g dayÀ1).
endothelium dysfunction and platelet activation observed in The cellular origin of MP was also assessed. In vitamin C- atherogenesis [8–12]. Evidence suggests that the antioxidant treated patients, the reduction in platelet-derived MP was 10% status is linked to the clinical expression of coronary artery higher (P ¼ 0.01). In patients with diabetes mellitus, dyslipi- disease [13]. Indeed, low vitamin C serum concentrations are demia or more than two cardiovascular risk factors, vitamin C associated with inflammation and severity of the illness [14,15].
decreased endothelial and platelet-derived MP levels by $70% Therefore, additional antioxidant treatments were proposed to and 13%, respectively. This early effect on circulating platelet reduce both platelet activation and endothelial dysfunction and endothelial-derived MP, testifies to the importance of during atherogenesis [16]. In various experimental models, oxidative stress during MI. Vitamin C could prove beneficial antioxidants were found to be beneficial on vasospasm, neoin- for the outcome of patients at higher thrombotic risk.
timal thickening or remodeling after balloon injury [17]. Ac-cordingly, antioxidant vitamin C treatment was shown to Keywords: atherosclerosis; oxidative stress; thrombosis.
improve endothelial function in several subsets of patientsincluding hypercholesterolemia, coronary artery disease andheart transplantation vasculopathy [18–22].
In this study, we examined whether additional treatment by vitamin C may reduce circulating procoagulant MP as a marker Membrane microparticles (MP) are shed from stimulated and/or of vascular damage and platelet activation in the peripheral apoptotic vascular cells and released in blood flow. They bear blood of patients with myocardial infarction (MI). The cell membrane glycoproteins testifying to their cell origin and their origin of MP was also assessed to detect a possible subset of amount was found to be correlated to the degree of apoptosis cells more responsive to vitamin C treatment. MP were isolated [1]. Elevated levels of circulating MP have been reported in a from plasma samples by capture onto immobilized annexin V, a variety of pathologies [1–4]. In the blood flow, circulating MP protein with high affinity for PhtdSer. MP measurements and provide an additional procoagulant phospholipid surface neces- characterization were performed using a modified prothrombi- sary for the assembly of the clotting enzymes complexes and nase assay [4]. Effects of vitamin C were examined with respectto various cardiovascular risk factors.
Correspondence: F. Toti, Institut d’He´matologie et d’Immunologie, Faculte´ de Me´decine, 4, rue Kirschleger 67085 Strasbourg cedex, France.
Tel.: þ 33 03 9024 3986; fax: þ 33 03 9024 4016; e-mail: Sixty-one patients presenting an acute myocardial infarction Received 18 April 2002, revised 11 July 2002, accepted 13 July 2002 were enrolled in the study. Typical chest pain, persistent # 2003 International Society on Thrombosis and Haemostasis ST–segment elevation on electrocardiogram, and a two-fold streptavidin-coated microtitration plates and Chromozym TH rise in creatine phosphokinase (CPK) diagnosed MI. All pati- were from Roche Diagnostics (Mannheim, Germany).
ents received conventional treatment including beta-blockers,aspirin (160–325 mg dayÀ1) before blood sampling. An addi- Isolation of circulating MP and determination of their tional weight-adjusted unfractionated heparin regimen was applied (initial bolus 50 units kgÀ1) to achieve an activatedpartial thromboplastin time between 60 and 90 s. Patients were Blood samples, collected by venous puncture, were collected on prospectively randomized to receive an additional 5 days’ vitamin 138 mmol LÀ1 citrated solution (9 volumes of blood : 1 volume of C oral treatment (1 g dayÀ1) or placebo tablets (29 and 32 patients, anticoagulant) before vitamin C therapy [day (D)1] and 5 days respectively). 76% of the patients treated by vitamin C and 75% of later (D5). Platelet-free plasma samples (PFP) containing circu- the patients with placebo were submitted to primary angioplasty.
lating MP were obtained by double centrifugation as previously Statins, anti-ischemic medications and anti-platelet inhibitors described [1]. MP were captured onto insolubilized annexin Vand were equally prescribed. The opportunity of angioplasty, stent their PhtdSer content was determined by functional prothrombi- placement and additional anti-GPIIbIIIa therapy (abciximab or nase assay using a microplate reader equipped with kinetics eptifibatide) was under the responsibility of independent angio- software. In this assay, blood clotting factors (FXa, FVa, FII) plasty physicians. Vitamin C was given just at the end of anti- and calcium concentrations were determined to ensure that GPIIbIIIa treatment. This treatment consisted of one bolus of PhtdSer is the rate-limiting parameter in the generation of soluble 250 mg kgÀ1 followed by 0.125 mg kgÀ1 minÀ1 continuous infu- thrombin from prothrombin. In this purified system, the presence sion up to 18 h for abciximab and one bolus of 180 mg kgÀ1 of TF on captured MP does not alter values corresponding to followed by initiation of 2 mg kgÀ1 minÀ1 continuous infusion PhtdSercontent, and FVawasinexcess with respect to FXa in order up to 18 h for eptifibatide. Patients with diabetes mellitus (DM) to exclude any contribution of FVa, possibly associated with MP.
were recruited on the basis of documented medical reports, if Results were expressed as nanomolar PhtdSer equivalent (nmol treated by insulin or oral hypoglycaemic agents, or when LÀ1 PhtdSer Eq) by reference to a standard curve constructed with elevated levels of fasting blood glucose (> 140 mg dLÀ1) were liposomes of known composition and concentration [1].
measured on at least two separate occasions. Dyslipidemicpatients (DL) were identified on the basis of medical history, Search for the cellular origin of circulating MP ongoing treatment by statins or fibrates, or high levels of totalor LDL cholesterol measured during their stay. Other cardio- Biotinylated monoclonal antibodies to various cell types (anti- vascular risk factors considered were arterial hypertension, CD31 for endothelial cells, anti-GPIb for platelets) were inso- current smoking, increase weight (body mass index >29 kg lubilized onto streptavidin-coated microtitration plates as pre- mÀ2). For comparative purpose, 23 patients with less than two viously described [4]. CD31 being also expressed to a small cardiovascular risk factors were defined as low-risk patients extent on platelets, it was previously ensured that circulating (referred to as LR in the text) regardless of the occurrence MP bearing CD31 ([CD31]þ MP) mainly originate from apop- of DM or DL. Thirty-eight patients with more than two cardi- totic endothelial cells and are therefore a reliable marker of ovascular risk factors, including DM and DL, were defined endothelial damage [7,23]. After incubation of PFP and wash- as high-risk patients (referred to as HR in the text). Fifty heal- ing, captured MP were quantified by prothrombinase assay as thy volunteers (HV) were simultaneously investigated du- described above. Background values obtained with correspond- ring the inclusion period as a reference group. Written ing irrelevant IgGs were subtracted. It should be emphasized informed consent was obtained from all the patients with the that no direct comparison between capture by annexin V and approval of local Ethical Committee (Comite´ Consultatif de antibodies could be performed because affinities for the respec- Protection des Personnes dans la Recherche Biome´dicale, tive counterpart ligands are different.
Results are expressed as mean Æ SEM from at least two Monoclonal antibody (mAb) to human platelet glycoprotein independent measurements. Patients groups were compared GPIb was a kind gift of Dr F. Lanza, biotinylated as described using a Mann–Whitney test. A P-value <0.05 was considered elsewhere [4]. Biotinylated mAb to CD31 was from CALTAG Laboratories (Burlingame, CA, USA), and the irrelevant cor-responding biotinylated immunoglobulins were from Leinco Technologies (Ballwin, MO, USA). Human prothrombin (FII)was from Hyphen BioMed (Andresy, France) and activated factor X (FXa) from Biogenic S.A. (Mauguio, France). Acti-vated factor V(FVa) was a product from American Diagnostica Clinical details, angiographic data and treatments are given in (Greenwich, UK). Biotinylated recombinant human annexin V Tables 1 and 2. Sex, risk factor distribution, median time to was the same as that used elsewhere [1]. High binding capacity therapy, localization of MI, multivessel disease, CPK peak, type # 2003 International Society on Thrombosis and Haemostasis Vitamin C, procoagulant microparticles and MI 173 Table 1 Baseline characteristics and medical history Fig. 1. Circulating procoagulant microparticles levels at day 5 Time from onset of pain to intervention (h) following Myocardial Infarction in vitamin C and placebo groups. Whole population (vitamin C: n ¼ 29; placebo: n ¼ 32), diabetes mellitus Left ventricular ejection fraction assessed (DM þ vitamin C: n ¼ 12; DM þ placebo n ¼ 11), dyslipidemic (DL þ vitamin C: n ¼ 18; DL þ placebo: n ¼ 18), high-risk patients(HR þ vitamin C: n ¼ 20; HR þ placebo: n ¼ 18). Microparticles werecaptured onto annexin V. MP procoagulant phospholipid content was measured as nanomolar phosphatidylserine equivalents (nmol LÀ1PhtdSer Eq) by functional prothrombinase assay.
Circulating procoagulant MP during myocardial infarction With respect to values measured in HV, patients with MI pre- sented high levels of procoagulant MP by capture onto annexin V (MI 13.2 Æ 1.85 vs. HV 2.3 Æ 0.2 nmol LÀ1 PhtdSer Eq).
Circulating MP were mainly of platelet (MI 3.2 Æ 0.54 vs.
HV 0.58 Æ 0.10 nmol LÀ1 PhtdSer Eq) and endothelial (MI 0.48 Æ 0.20 vs. HV 0.02 Æ 0.006 nmol LÀ1 PhtdSer Eq) origin.
Values of circulating MP levels according to various risk factors Coronary perfusion was assessed by TIMI flow scoring as defined by the Effect of additional vitamin C treatment on procoagulant Thrombolysis in myocardial infection study. TIMI 0 is defined by the absence of antegrade flow, TIMI 1 by penetration of contrast withuncompleted opacification of the coronary vascular bed. ASA, acetylsa- In the whole subset of patients with MI, the additional treatment by vitamin C resulted in a slight ($14%) decrease in procoa-gulant MP captured onto annexin V, while an $4% reduction of therapy were not statistically different between vitamin C- was evidenced in the placebo group (Fig. 1). MP measurements treated and untreated groups. At D1 after MI and before vitamin C in treated or untreated patients, did not reach statistical differ- administration, a non-significant difference between patients to ence at D5 (vitamin C 10.8 Æ 1.3 vs. placebo 13.3 Æ 1.7 be treated by placebo and those to be treated by vitamin C was nmol LÀ1 PhtdSer Eq). Interestingly, a significant difference observed, the latter subset presenting a 11% lower mean value was evidenced between untreated and vitamin C-treated DM of circulating MP captured onto annexin V (vitamin C 12.45 Æ patients who presented lower MP levels at D5 (DM þ vitamin C 1.9 vs. placebo 13.9 Æ 1.9 nmol LÀ1 PhtdSer Eq, P ¼ 0.57). This 12.7 Æ 2.6 vs. DM þ placebo 20.8 Æ 3.8 nmol LÀ1 PhtdSer Eq; slight difference probably results from prospective randomiza- P ¼ 0.05). Dyslipidemic and patients at high risk (HR) followed tion. As the treatments applied were distributed equally between a similar pattern although to a lesser extent (DL þ vitamin C both subsets, they could hardly account for this observation.
9.9 Æ 1.3 vs. DL þ placebo 15.7 Æ 2.5 nmol LÀ1 PhtdSer Eq; Table 3 Cell origin of circulating MP at day 1 after MI in diabetes mellitus (DM)(n ¼ 23), dyslipidemic (DL)(n ¼ 36) and high-risk (HR) patients(n ¼ 38). HV corresponds to healthy volunteers (n ¼ 50). No significant difference in the amount of circulating MP appeared at randomization betweenvitamin C and placebo group. Circulating MP were captured on antibodies to platelet (GPIb) or endothelial (CD31) membrane antigens. Procoagulantphospholipid content was measured by functional prothrombinase assay, and expressed as nanomolar phosphatidylserine equivalents (nmol LÀ1 PhtdSer Eq) Circulating microparticles during myocardial infarction (day 1) (nM PhtdSer Eq) # 2003 International Society on Thrombosis and Haemostasis Fig. 2. Circulating procoagulant microparticles levels at day 5 followingMyocardial Infarction in diabetes mellitus and low-risk patients (LR).
Fig. 3. Platelet-derived microparticles levels at day 5 following Diabetes mellitus (DM þ vitamin C: n ¼ 12; DM þ placebo n ¼ 11), Myocardial Infarction in vitamin C and placebo groups. Whole population low-risk patients (LR þ vitamin C: n ¼ 13; LR þ placebo: n ¼ 10).
(vitamin C: n ¼ 29; placebo: n ¼ 32), diabetes mellitus (DM vitamin C: n Microparticles were captured onto annexin V. MP procoagulant ¼ 12; DM placebo: n ¼ 11), dyslipidemic (DL þ vitamin C: n ¼ 18; DL þ phospholipid content was measured as nanomolar phosphatidylserine placebo: n ¼ 18), high-risk patients (HR þ vitamin C: n ¼ 20; HR þ equivalents (nM PhtdSer Eq) by functional prothrombinase assay.
placebo: n ¼ 18). Microparticles were captured onto anti-GPIb antibody.
MP procoagulant phospholipid content was measured as nanomolarphosphatidylserine equivalents (nM PhtdSer Eq) by functional P ¼ ns)(HR þ vitamin C 11.0 Æ 1.8 vs. HR þ placebo 16.2 Æ 2.5 nmol LÀ1 PhtdSer Eq; P ¼ ns)(Fig. 1). In these two subsetsof patients, placebo administration was associated with an$12% elevation in MP levels captured onto annexin V, to be did not reach statistical significance at D5 (vitamin C 0.14 Æ compared with the 28% elevation measured in DM patients.
0.02; placebo 0.39 Æ 0.18 nmol LÀ1 PhtdSer Eq). In HR or DL Interestingly, in patients at lower risk (LR), circulating procoa- patients significantly lower levels were, however, detected upon gulant MP at D5 were reduced to the same extent in the presence vitamin C treatment (DL þ vitamin C 0.12 Æ 0.03 vs. DL þ or absence of additional vitamin C treatment, suggesting its placebo 0.59 Æ 0.3 nmol LÀ1 PhtdSer Eq; P ¼ 0.05; HR þ vita- inefficiency on MP release (placebo À34% and vitamin C min C 0.11 Æ 0.03 vs. HR þ placebo 0.56 Æ 0.28 nmol LÀ1 PhtdSer Eq; P ¼ 0.04). In addition, a drastic elevation($60%) in circulating endothelial-derived MP was measuredin DM patients at D5 after placebo administration, whereas an Effect of additional vitamin C treatment on platelet-derived $70% reduction was observed after vitamin C treatment (DM þ vitamin C 0.12 Æ 0.03 vs. DM þ placebo 0.97 Æ 0.7 Platelet-derived MP levels measured after capture onto GPIb nmol LÀ1 PhtdSer Eq; P ¼ 0.06)(Fig. 4). As observed for plate- antibody appeared decreased in vitamin C-treated patients let-derived MP, a reduction in endothelial-derived MP was regardless of the risk factor (vitamin C 2.2 Æ 0.4 vs. placebo conversely found in LR patients, regardless of the treatment, 3.6 Æ 0.5 nmol LÀ1 PhtdSer Eq, P ¼ 0.01). However, the extent 67% and 50%, respectively, for vitamin C or placebo, the dif- of the reduction varied with the clinical background. In ference between the two subsets being-non-significant (LR þ untreated DM and HR patients, platelet-derived MP levels vitamin C 0.15 Æ 0.02 vs. LR þ placebo 0.35 Æ 0.19 nmol LÀ1 showed an $43% drastic increase after 5 days of placebo administration reflecting an ongoing process of platelet stimu-lation (HR þ vitamin C 1.7 Æ 0.3 vs. HR þ placebo 3.9 Æ 0.7nmol LÀ1 PhtdSer Eq; DM þ vitamin C 3.0 Æ 0.6 vs. DM þplacebo 4.3 Æ 1.1 nmol LÀ1 PhtdSer Eq) (Fig. 3). In patients atlower risk (LR), neither placebo nor vitamin C administrationled to elevated platelet-derived MP; on the contrary, a reductionwas observed in both cases, the difference between both subsetsbeing non-significant (LR þ vitamin C 3.37 Æ 0.73 vs. LR þplacebo 3.22 Æ 0.38 nmol LÀ1 PhtdSer Eq, P ¼ ns).
Effect of additional vitamin C treatment on endothelial-derived MP during MI Fig. 4. Endothelial-derived microparticles levels at day 5 followingMyocardial Infarction in vitamin C and placebo group. Whole population Within the whole population of MI patients, a reduction of (vitamin C: n ¼ 29; placebo: n ¼ 32), diabetes mellitus (DM þ vitamin C: $65% in circulating endothelial-derived MP, captured onto n ¼ 12; DM þ placebo: n ¼ 11), dyslipidemic (DL þ vitamin C: n ¼ 18; anti-CD31 antibody, was evidenced after vitamin C treatment DL þ placebo: n ¼ 18), high-risk patients (HR þ vitamin C: n ¼ 20; HR þplacebo: n ¼ 18). Microparticles were captured onto anti-CD31 antibody whereas only an $29% decrease could be evidenced after and their procoagulant phospholipid content measured by functional 5 days of placebo administration. Nevertheless, endothelial- prothrombinase assay as nanomolar phosphatidylserine equivalents derived MP levels measured in treated and untreated patients # 2003 International Society on Thrombosis and Haemostasis Vitamin C, procoagulant microparticles and MI 175 ed in acute coronary syndrome [33], pointing to underlying endothelial apoptosis. In our study, endothelial-derived MP In patients with MI taken as a whole population, the benefit of were decreased by vitamin C treatment in DM, HR and DL additional oral vitamin C treatment could appear modest with a patients (70% reduction in DM), suggesting a major red- 14% decrease in circulating procoagulant MP levels compared uction in endothelial damage (Fig. 4). In DM, results are to the 4% reduction in patients with conventional treatment.
in accordance with the beneficial effects of vitamin C pre- These measurements, performed after capture onto immobi- viously demonstrated on endothelial function [18,34]. In- lized annexin V, might underestimate MP populations present- creased apoptosis and high oxidative stress are two features ing a proportion of oxidized phospholipids restricting binding to of DM [35]. Various serum factors, namely oxLDL, reactive annexin V [24]. However, this limitation appears negligible in oxygen species (ROS), angiotensin II, hyperglycemia-mediated view of MP levels measured in clinical subsets in which high superoxide induced endothelial cell apoptosis through en- oxidative stress may account for enhanced cellular activation. A hanced intracellular oxidative stress could be responsive to significant elevation in circulating MP captured onto annexin V the treatment [29]. In patients with congestive heart failure, was detected in DM as well as the clear decrease upon vitamin C vitamin C and carvedilol were both found to reduce endothelial treatment. Furthermore, the inhibitory effect of vitamin C on cell apoptosis, circulating levels of MP, and markers of oxida- procoagulant MP release was not observed in patients at lower risk (Fig. 2). In LR patients, amounts of circulating procoagu- The drastic effect of additional vitamin C treatment on lant MP were decreased to the same extent 5 days after vitamin endothelial-derived MP measured in DM patients emphasizes C or placebo administration. These opposite responses to the specific role of endothelial apoptosis induced by ROS in vitamin C treatment observed in DM and LR patients could such a pathology. As an observation added in proof, no mod- reflect a specific contribution of oxidative stress to vascular cell ification in leukocyte-derived MP could be evidenced with stimulation and MP release in HR patients. In LR patients, respect to values measured in HV (data not shown). In DM, oxidative stress might be overwhelmed by other stimuli such as ROS could contribute to endothelium dysfunction by reducing cytokines, shear stress, thrombin and tissue factor occurring, bioavailability of NO [36,37], a potent mitochondrial mem- generated or expressed during MI [25]. These observations brane stabilizer [38,39], crucial for endothelial survival. ROS confirm procoagulant MP as a relevant parameter to follow could also promote the release of mitochondrial cytochrome c an ongoing process of vascular damage during MI in patients at Shed MP originating from apoptotic endothelial cells or In accordance with previous reports from our group and activated platelets are not only considered markers of vascular others, platelet- and endothelial-derived MP appear to be the damage but also behave as cellular effectors disseminating two main sources of procoagulant MP released during MI [6,7].
proinflammatory, pro-adhesive, pro-apoptotic and prothrombo- Unexpectedly, additional vitamin C treatment resulted in a 14% tic potentials in the vasculature [41–45]. Recently, various decrease in platelet-derived MP levels in spite of anti-platelet phospholipids borne by MP shed from apoptotic endothelial and antithrombin therapy. In DM and HR patients, although the cells were found susceptible to oxidation and able to elicit reduction after 5 days of vitamin C administration could appear specific responses by vascular cells [24,46]. Furthermore, MP modest per se (3% and 10%, respectively), it has to be compared isolated from patients with MI selectively impair the endothe- to the dramatic elevation in MP levels measured after placebo lial NO transduction pathway [47]. Each MP population re- administration (up to 44%). Thus, vitamin C prevents an on- leased into the blood flow may have a specific contribution to going process of platelet activation and membrane shedding in the process of MI, which remains to be characterized. Likewise, the susceptibility of membrane phospholipids and cells to Diminished platelet aggregation and adhesion by vitamin C oxidative stress probably differs with the lineage, explaining has been evoked in previous studies [10,26,27]. In patients with the variety of the vascular responses [48]. These observations chronic heart failure, vitamin C enhanced platelet responsive- lead to consider procoagulant circulating MP as an eventual ness to the anti-aggregatory effects of NO donors, reduced target for a pharmacological control in patients at high throm- plasma lipid-derived free radicals and improved endothelial function [28]. Various mechanisms may contribute to these Our data suggest that an early additional antioxidant treat- observations: (i) the formation of guanylate cyclase activation ment may improve endothelial function particularly in subsets and cGMP formation, a potent platelet inhibitor [29]; and (ii) of patients in which high oxidative stress was previously inhibition of inflammatory platelet activating factor mimetics demonstrated, such as DL and DM groups. According to preventing the formation of platelet-leukocytes aggregates and the current understanding, vitamin C could promote an early improvement of the cellular redox imbalance and prevent Although representing a smaller proportion, endothelial- NO inactivation in the vascular compartment. The associated derived MP appeared highly susceptible to vitamin C treatment.
reduction in platelet activation, as evidenced by MP mea- We previously showed that circulating endothelial-derived surements, although less sensitive to antioxidant treatment, MP testify to endothelial activation and/or apoptosis [7,32].
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